Chronic cocaine administration leads to changes in brain function that persist long after the acute withdrawal phase. The acoustic startle response (ASR) is a well characterized reflexive response to a sudden acoustic stimulus. The ASR is mediated by a simple 3-synapse subcortical circuit; it is modulated in part by brain areas and neurotransmitters associated with cocaine administration. Our initial study and subsequent replication reveals a profound diminution of the ASR in cocaine-dependent subjects after a brief period of abstinence. Little is known about the exact time course during which this robust abnormality develops. Work using rodent models by our group and others also indicates a reduction in the ASR after recurrent cocaine administration that is consistent with our clinical finding. However, we cannot be certain that startle reductions in these subjects did not, at least in part, predate their cocaine addiction as a vulnerability factor. Our preliminary findings indicate that first degree relatives of cocaine-dependent subjects also have reduced startle compared to healthy controls. The findings of low ASR in rats and humans during cocaine washout and low ASR in family members suggests there may be both a trait and state component of the startle reductions we have reported. We propose a translational project with both clinical and preclinical components that will advance our understanding of the clinical significance and underlying pathophysiology of cocaine-related startle reduction. The central objectives of this proposal are to dissect this finding with regard to its development and persistence in early and later phases of cocaine abstinence in humans (Specific Aims 1 and 2) and in rats (Specific Aims 5); to ascertain whether startle reduction and its potential normalization during later abstinence is a predictor of clinical course in human subjects with cocaine dependence (Specific Aim 3); and to examine whether startle reduction is, at least in part, a vulnerability trait for the development of cocaine dependence (Specific Aim 4). This latter Aim will be carried out in humans by testing siblings of cocaine-dependent subjects, and in rats by evaluating vulnerability to cocaine self-administration in high- vs. low-startling rats. Relevance to Public Health: Cocaine dependence is an enormous public health problem. The significance of this work lies in the potential for the ASR reduction to serve as a reliable, easily repeatable biological measure of cocaine-induced brain changes that may enhance outcome prediction so that tailored treatments may be directed at those patients most vulnerable to relapse, given the restriction of resources available for substance abuse treatment. [unreadable] [unreadable] [unreadable]